Decay of heterochromatin domains at selective gene loci in aging mouse brain cells

Aging is characterized by a progressive decline of organismal function and increase in vulnerability to diseases. Loss of heterochromatin during aging has been observed in a variety of organisms, however, understanding its role in aging-related phenotypes has been limited by the lack of information about the specific cell types and gene loci affected by this type of epigenetic changes. To address this bottleneck, we probed dynamic changes in chromatin landscape at single cell resolution in the forebrain, hippocampus, heart, skeletal muscle and bone marrows from 3-month, 10-month and 18-month-old mice, and characterized age-associated changes in chromatin accessibility at over 300,000 candidate regulatory elements across 34 major cell types. We report that excitatory neurons displayed profound changes in a specific set of heterochromatin domains during aging, evidenced by an increase in chromatin accessibility, a decrease in the heterochromatin marker H3K9me3, and de-repression of non-coding RNA species. These results suggest that heterochromatin maintenance are impaired in aging excitatory neurons, and this may be associated with increased repetitive element activity and neurodegenerative diseases. We collected the dorsal hippocampus, frontal cortex, heart, leg muscles and bone marrow from male C57BL/6JN mice in three age groups, namely 3-month, 10-month, and 18-month, and performed single-nucleus ATAC-seq to profile open chormatin changes during aging. We also performed single-nucleus RNA-seq and paired-tag for H3K9me3 on dorsal hippocampus and frontal cortex.